Articular, monoclonal gamma3 heavy-chain deposition disease: characterization of a partially deleted heavy-chain gene and its protein product synthesized in vivo and in vitro.

摘要

Objective A patient presented with heavy-chain deposition disease (HCDD), exhibiting severe erosive polyarthropathy caused by synovial deposits of abnormal monoclonal, heavily deleted free 3 heavy chains lacking the VH and CH1 domains. The absence of VH was surprising, since it is considered important for pathogenic tissue deposition. This study was undertaken to analyze the genetic structure of the heavy chain, the protein product synthesized in vitro, and that deposited in the synovium in comparison with the serum and urinary proteins. Methods Hybridomas were made by fusion of blood and bone marrow mononuclear cells with mouse myeloma cells. Cloned B cell hybridomas secreting 3 were selected and analyzed by polymerase chain reaction. Purified hybridoma Ig was sequenced by Edman degradation. Antiserum raised to a peptide corresponding to residues 2-15 of the truncated VH was used in Western blots of synovial tissue. Results The hybridomas secreted free 3 chains consisting of a VH4 gene truncated 21 nucleotides into the first complementarity-determining region and then reading straight into the hinge region. The amino acid sequence confirmed the presence of residues 1-32 of the VH4 gene. Immunoblotting of synovial tissue showed the presence of Ig with truncated VH. Conclusion The 3 heavy chain had a deletion of VH from codon 33 and of the entire CH1. In vivo, the 32 VH amino acids were proteolytically degraded. In the joint, however, the 32 residues of VH remained intact, consistent with a pathogenic role of VH for tissue deposition. To our knowledge, this is the first reported case of HCDD causing an erosive, polyarticular arthropathy as the dominating clinical feature.